Skip to main content

Advertisement

SpringerLink
Log in

Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Although the recent development of direct KRASG12C inhibitors (G12Ci) has improved outcomes in KRAS mutant cancers, responses occur only in a fraction of patients, and among responders acquired resistance invariably develops over time. Therefore, the characterization of the determinants of acquired resistance is crucial to inform treatment strategies and to identify novel therapeutic vulnerabilities that can be exploited for drug development.

Recent Findings

Mechanisms of acquired resistance to G12Ci are heterogenous including both on-target and off-target resistance. On-target acquired resistance includes secondary codon 12 KRAS mutations, but also acquired codon 13 and codon 61 alterations, and mutations at drug binding sites. Off-target acquired resistance can derive from activating mutations in KRAS downstream pathway (e.g., MEK1), acquired oncogenic fusions (EML4-ALK, CCDC176-RET), gene level copy gain (e.g., MET amplification), or oncogenic alterations in other pro-proliferative and antiapoptotic pathways (e.g., FGFR3, PTEN, NRAS). In a fraction of patients, histologic transformation can also contribute to the development of acquire resistance.

Summary

We provided a comprehensive overview of the mechanisms that limit the efficacy of this G12i and reviewed potential strategies to overcome and possibly delay the development of resistance in patients receiving KRAS directed targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol. 2021;12(4):217–37. https://doi.org/10.5306/wjco.v12.i4.217.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–8. https://doi.org/10.1093/annonc/mdz167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ricciuti B, Leonardi GC, Metro G, et al. Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications. Expert Rev Respir Med. 2016;10(1):53–68. https://doi.org/10.1586/17476348.2016.1115349.

    Article  PubMed  CAS  Google Scholar 

  4. Ricciuti B, Alessi JV, Elkrief A, et al. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer. Ann Oncol. 2022;33(10):1029–40. https://doi.org/10.1016/j.annonc.2022.07.005.

    Article  PubMed  CAS  Google Scholar 

  5. Di Federico A, De Giglio A, Gelsomino F, Sperandi F, Melotti B, Ardizzoni A. Predictors of survival to immunotherapy and chemoimmunotherapy in non-small cell lung cancer: A meta-analysis. J Natl Cancer Inst. 2023;115(1):29–42. https://doi.org/10.1093/jnci/djac205.

    Article  PubMed  CAS  Google Scholar 

  6. Ricciuti B, Arbour KC, Lin JJ, et al. Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status. J Thorac Oncol. 2022;17(3):399–410. https://doi.org/10.1016/j.jtho.2021.10.013.

    Article  PubMed  CAS  Google Scholar 

  7. Di Federico A, De Giglio A, Parisi C, Gelsomino F. STK11/LKB1 and KEAP1 mutations in non-small cell lung cancer: Prognostic rather than predictive? Eur J Cancer. 2021;157:108–13. https://doi.org/10.1016/j.ejca.2021.08.011.

    Article  PubMed  CAS  Google Scholar 

  8. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120–31. https://doi.org/10.1056/NEJMoa2204619. In this phase II trial, Janne PA et al. demonstrated the clinical efficacy of adagrasib, an irreversible, covalent inhibitor of KRAS G12C, in patients with advanced non-small cell lung cancer that progressed to previous treatment with immune-checkpoint inhibitors, alone or in combination with chemotherapy.

    Article  PubMed  Google Scholar 

  9. Dy GK, Govindan R, Velcheti V, et al. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. J Clin Oncol. 2023:JCO2202524. https://doi.org/10.1200/JCO.22.02524. This phase II trial demonstrated the clinical efficacy of Sotorasib, an irreversible, covalent inhibitor of KRAS G12C, in patients with advanced non-small cell lung cancer that progressed to previous treatment with immunecheckpoint inhibitors, alone or in combination with chemotherapy.

  10. Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A. 1982;79(11):3637–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Della Porta G, Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science. 1984;223(4637):661–4. https://doi.org/10.1126/SCIENCE.6695174.

    Article  PubMed  CAS  Google Scholar 

  12. Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep Med. 2021;2(1):100186. https://doi.org/10.1016/j.xcrm.2020.100186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Palma G, Khurshid F, Lu K, Woodward B, Husain H. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. NPJ Precis Oncol. 2021;5(1) https://doi.org/10.1038/S41698-021-00237-5.

  14. Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978. https://doi.org/10.1016/J.CTRV.2020.101978.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51. https://doi.org/10.1038/NATURE12796.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ricciuti B, Mira A, Andrini E, et al. How to manage KRAS G12C-mutated advanced non-small-cell lung cancer. Drugs Context. 2022;11:1–11. https://doi.org/10.7573/DIC.2022-7-4.

    Article  Google Scholar 

  17. Weiss A, Lorthiois E, Barys L, et al. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C. Cancer Discov. 2022;12(6):1500–17. https://doi.org/10.1158/2159-8290.CD-22-0158.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sacher A, Patel MR, Miller WH Jr, et al. Phase Ia study to evaluate GDC-6036 monotherapy in patients with non-small cell lung cancer (NSCLC) with KRAS G12C mutation. In: Presented at: 2022 World Conference on Lung Cancer. Vienna, Austria; 2022.

  19. Christensen JG, Olson P, Briere T, Wiel C, Bergo MO. Targeting Krasg12c -mutant cancer with a mutation-specific inhibitor. J Intern Med. 2020;288(2):183–91. https://doi.org/10.1111/JOIM.13057.

    Article  PubMed  CAS  Google Scholar 

  20. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014;13(11):828–51. https://doi.org/10.1038/NRD4389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gustafson WC, Wildes D, Rice MA, et al. Direct targeting of RAS in pancreatic ductal adenocarcinoma with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI(ON) inhibitor. J Clin Oncol. 2022;40(4_suppl):591–1.

    Article  Google Scholar 

  22. Nichols RJ, Yang YC, Cregg J, et al. RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting, vol. 2022; 2022. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3595.

    Google Scholar 

  23. Burns MC, Sun Q, Daniels RN, et al. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci U S A. 2014;111(9):3401–6. https://doi.org/10.1073/PNAS.1315798111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Maurer T, Garrenton LS, Oh A, et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci U S A. 2012;109(14):5299–304. https://doi.org/10.1073/PNAS.1116510109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Hillig RC, Sautier B, Schroeder J, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A. 2019;116(7):2551–60. https://doi.org/10.1073/pnas.1812963116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hofmann MH, Gmachl M, Ramharter J, et al. BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov. 2021;11(1):142–57. https://doi.org/10.1158/2159-8290.CD-20-0142.

    Article  PubMed  CAS  Google Scholar 

  27. Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218(1):e20201414. https://doi.org/10.1084/jem.20201414.

    Article  PubMed  CAS  Google Scholar 

  28. Anastasiou P, Mugarza E, Boumelha J, Rana S, Moore C, Molina-Arcas M, Downward J. Abstract 4029: Combination of KRASG12C(ON) and SHP2 inhibitors overcomes adaptive resistance and enhances anti-tumor immunity. Cancer Res. 2022;82(12_Supplement):4029. https://doi.org/10.1158/1538-7445.AM2022-4029.

    Article  Google Scholar 

  29. Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170(1):17–33. https://doi.org/10.1016/J.CELL.2017.06.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016;165(3):643–55. https://doi.org/10.1016/J.CELL.2016.03.045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Veluswamy R, Bhalla S, Samstein R, et al. Phase I/II trial of rigosertib and nivolumab for KRAS mutated non-small cell lung cancer (NSCLC) patients. Ann Oncol. 33:S1019–20.

  32. Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604–8. https://doi.org/10.1126/SCIENCE.AAD6204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Patricelli MP, Janes MR, Li LS, et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov. 2016;6(3):316–29. https://doi.org/10.1158/2159-8290.CD-15-1105.

    Article  PubMed  CAS  Google Scholar 

  34. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. https://doi.org/10.1038/S41586-019-1694-1.

    Article  PubMed  CAS  Google Scholar 

  35. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020;383(13):1207–17. https://doi.org/10.1056/NEJMOA1917239.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. FDA FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc .

  37. Lumykras | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/lumykras#authorisation-details-section .

  38. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733–46. https://doi.org/10.1016/S0140-6736(23)00221-0.

    Article  PubMed  Google Scholar 

  39. Awad M, Pelizzari G, Stevenson JP, et al. Sotorasib in advanced KRAS p.G12C-mutated non-small cell lung cancer (NSCLC): Safety and efficacy data from the global expanded access program (EAP). Ann Oncol. 2022;33(suppl 7):S448–554.

    Google Scholar 

  40. FDA FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc .

  41. Sebastian M, Eberhardt WEE, Hoffknecht P, et al. KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer. 2021;154:51–61. https://doi.org/10.1016/J.LUNGCAN.2021.02.005.

    Article  PubMed  CAS  Google Scholar 

  42. Cui W, Franchini F, Alexander M, et al. Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer. Lung Cancer. 146:310–7.

  43. Wu MY, Zhang EW, Strickland MR, et al. Clinical and Imaging Features of Non-Small Cell Lung Cancer with G12C KRAS Mutation. Cancers. 2021;13(14) https://doi.org/10.3390/CANCERS13143572.

  44. Vassella E, Kashani E, Zens P, et al. Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations. Eur J Cancer. 2021;159:227–36. https://doi.org/10.1016/J.EJCA.2021.10.006.

    Article  PubMed  CAS  Google Scholar 

  45. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, et al. Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16(6):e270–8. https://doi.org/10.1016/S1470-2045(15)70057-4.

    Article  PubMed  Google Scholar 

  46. Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. 2022;40(17_suppl):LBA9009–9. https://doi.org/10.1200/JCO.2022.40.17_SUPPL.LBA9009.

  47. Lamberti G, Aizer A, Ricciuti B, et al. Incidence of Brain Metastases and Preliminary Evidence of Intracranial Activity With Sotorasib in Patients With KRASG12C-Mutant Non-Small-Cell Lung Cancer. JCO Precis Oncol. 2023;7(7) https://doi.org/10.1200/PO.22.00621.

  48. Koster KL, Appenzeller C, Lauber A, Früh M, Schmid S. Sotorasib Shows Intracranial Activity in Patients with KRAS G12C- Mutated Adenocarcinoma of the Lung and Untreated Active Brain Metastases. Case Rep Oncol. 2022;15(2):720–5. https://doi.org/10.1159/000525341.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Li B, Falchook GS, Durm GA, et al. OA03.06 CodeBreaK 100/101: First report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. J Thorac Oncol. 2022;17:S10–1.

    Article  Google Scholar 

  50. Jänne PA, Smit EF, de Marinis F, et al. LBA4 - Preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Ann Oncol. 2022;16(suppl_1):100104–4. https://doi.org/10.1016/iotech/iotech100104.

    Article  Google Scholar 

  51. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.

    Article  PubMed  CAS  Google Scholar 

  52. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829–38. https://doi.org/10.1056/NEJMoa1704795.

    Article  PubMed  CAS  Google Scholar 

  53. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121–6. https://doi.org/10.1093/annonc/mdz131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Negrao MV, Araujo HA, Lamberti G, et al. Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC. Cancer Discov. 2023; https://doi.org/10.1158/2159-8290.CD-22-1420. Negrao MV et al. investigated the genomic mechanisms of primary resistance to KRAS G12C inhibitors in patients with advanced NSCLC, identifying co-occurring genomic alterations in KEAP1, SMARCA4 and CDKN2A as independent factor of poor prognosis and providing the rationale for further combination therapies in this setting.

  55. Addeo A, Banna GL, Friedlaender A. KRAS G12C Mutations in NSCLC: From Target to Resistance. Cancers. 2021;13(11):2541. https://doi.org/10.3390/cancers13112541.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another Effector Pathway. Genes Cancer. 2011;2(3):261–74. https://doi.org/10.1177/1947601911408079.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–91. https://doi.org/10.1038/nrclinonc.2018.28.

    Article  PubMed  CAS  Google Scholar 

  58. Xue JY, Zhao Y, Aronowitz J, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421–5. https://doi.org/10.1038/s41586-019-1884-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, et al. Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition. Clin Cancer Res. 2020;26(7):1633–43. https://doi.org/10.1158/1078-0432.CCR-19-3523.

    Article  PubMed  CAS  Google Scholar 

  60. Lou K, Steri V, Ge AY, et al. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal. 2019;12(583):eaaw9450. https://doi.org/10.1126/scisignal.aaw9450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218(1):e20201414. https://doi.org/10.1084/jem.20201414.

    Article  PubMed  CAS  Google Scholar 

  62. Liu C, Lu H, Wang H, et al. Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling. Clin Cancer Res. 2021;27(1):342–54. https://doi.org/10.1158/1078-0432.CCR-20-2718.

    Article  PubMed  CAS  Google Scholar 

  63. Thatikonda V, Lu H, Jurado S, et al. Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C -driven cancers by addressing intrinsic and acquired resistance. bioRxiv. 2023; https://doi.org/10.1101/2023.01.23.525210.

  64. Awad MM, Liu S, Rybkin II, et al. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021;384(25):2382–93. https://doi.org/10.1056/NEJMoa2105281. Awad MM et al. investigated mechanisms of acquired resistance to KRAS G12C inhibitors in patients with advanced NSCLC and advanced gastro-intestinal tumors, discovering a wide spectrum of on-target, off-target and histologic mechanisms that promote acquired resistance to these agents after response or a period of disease control.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Tanaka N, Lin JJ, Li C, et al. Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation. Cancer Discov. 2021 Aug;11(8):1913–22. https://doi.org/10.1158/2159-8290.CD-21-0365.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Zhao Y, Murciano-Goroff YR, Xue JY, et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature. 2021;599(7886):679–83. https://doi.org/10.1038/s41586-021-04065-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Alessandro Di Federico, Federica Pecci & Biagio Ricciuti

  2. Department of Medical and Surgical Sciences, University of Bologna, Via Albertoni, 15, 40138, Bologna, Italy

    Alessandro Di Federico, Ilaria Ricciotti, Valentina Favorito, Andrea De Giglio & Giuseppe Lamberti

  3. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology, Center, University of Torino, Via Nizza 52, 10126, Torino, Italy

    Sandra Vietti Michelina, Pietro Scaparone & Chiara Ambrogio

  4. Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera di Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy

    Giulio Metro

Authors
  1. Alessandro Di Federico
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilaria Ricciotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentina Favorito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandra Vietti Michelina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pietro Scaparone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giulio Metro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrea De Giglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Federica Pecci
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Lamberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chiara Ambrogio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Biagio Ricciuti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alessandro Di Federico or Biagio Ricciuti.

Ethics declarations

Conflict of Interest

BR: served in advisory board for Regeneron and AstraZeneca. The remaining authors have no conflicts of interest to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Di Federico, A., Ricciotti, I., Favorito, V. et al. Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer. Curr Oncol Rep 25, 1017–1029 (2023). https://doi.org/10.1007/s11912-023-01436-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-023-01436-y

Keywords

Search

Navigation